In vivo resistance to the action of insulin on glucose disposal is commonly found in obese subjects. The mechanism for this does not appear to be solely an inhibition of glucose metabolism by fatty acids released from the enlarged fat stores. This has lead us to assess the role of obesity associated changes in skeletal muscle in in vivo "insulin resistance", since glucose disposal after an oral or IV glucose load is into this tissue. We have assessed the relationship of insulin resistance, degree of obesity, and skeletal muscle morphology in Pima and Caucasian non-diabetic men. We have found a significant correlation between capillary density in skeletal muscle and in vivo insulin action. We suggest that the increased diffusion distances created by muscle cell enlargement are part of the mechanism by which obesity is associated with "insulin resistance". Furthermore, the finding may explain the nonlinear relationship of insulin action and degree of obesity. The association of increased plasma glucose with obesity and capillary density may reflect a compensatory mechanism to overcome reduced glucose disposal. This compensatory mechanism has the potential, however, for producing adverse effects if prolonged. We conclude the changes in fat-free mass induced by obesity are as important metabolically as changes that occur in the fat compartment.